MiR-142-3p is downregulated in aggressive p53 mutant mouse models of pancreatic ductal adenocarcinoma by hypermethylation of its locus

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive disease with poor prognostic implications. This is partly due to a large proportion of PDACs carrying mutations in TP53, which impart gain-of-function characteristics that promote metastasis. There is evidence that microRNAs (miRNAs) may play a role in both gain-of-function TP53 mutations and metastasis, but this has not been fully explored in PDAC. Here we set out to identify miRNAs which are specifically dysregulated in metastatic PDAC. To achieve this, we utilised established mouse models of PDAC to profile miRNA expression in primary tumours expressing the metastasis-inducing mutant p53R172H and compared these to two control models carrying mutations, which promote tumour progression but do not induce metastasis. We show that a subset of miRNAs are dysregulated in mouse PDAC tumour tissues expressing mutant p53R172H, primary cell lines derived from mice with the same mutations and in TP53 null cells with ectopic expression of the orthologous human mutation, p53R175H. Specifically, miR-142-3p is downregulated in all of these experimental models. We found that DNA methyltransferase 1 (Dnmt1) is upregulated in tumour tissue and cell lines, which express p53R172H. Inhibition or depletion of Dnmt1 restores miR-142-3p expression. Overexpression of miR-142-3p attenuates the invasive capacity of p53R172H-expressing tumour cells. MiR-142-3p dysregulation is known to be associated with cancer progression, metastasis and the miRNA is downregulated in patients with PDAC. Here we link TP53 gain-of-function mutations to Dnmt1 expression and in turn miR-142-3p expression. Additionally, we show a correlation between expression of these genes and patient survival, suggesting that they may have potential to be therapeutic targets

In vitro synergy and enhanced murine brain penetration of saquinavir coadministered with mefloquine.

Highly active antiretroviral therapy has substantially improved prognosis in human immunodeficiency virus (HIV). However, the integration of proviral DNA, development of viral resistance, and lack of permeability of drugs into sanctuary sites (e.g., brain and lymphocyte) are major limitations to current regimens. Previous studies have indicated that the antimalarial drug chloroquine (CQ) has antiviral efficacy and a synergism with HIV protease inhibitors. We have screened a panel of antimalarial compounds for activity against HIV-1 in vitro. A limited efficacy was observed for CQ, mefloquine (MQ), and mepacrine (MC). However, marked synergy was observed between MQ and saquinavir (SQV), but not CQ in U937 cells. Furthermore, enhancement of the antiviral activity of SQV and four other protease inhibitors (PIs) by MQ was observed in MT4 cells, indicating a class specific rather than a drug-specific phenomenon. We demonstrate that these observations are a result of inhibition of multiple drug efflux proteins by MQ and that MQ also displaces SQV from orosomucoid in vitro. Finally, coadministration of MQ and SQV in CD-1 mice dramatically altered the tissue distribution of SQV, resulting in a >3-fold and >2-fold increase in the tissue/blood ratio for brain and testis, respectively. This pharmacological enhancement of in vitro antiviral activity of PIs by MQ now warrants further examination in vivo

Sitting too much: a hierarchy of socio-demographic correlates

Too much sitting (extended sedentary time) is recognized as a public health concern in Europe and beyond. Time spent sedentary is influenced and conditioned by clusters of individual-level and contextual (upstream) factors. Identifying population subgroups that sit too much could help to develop targeted interventions to reduce sedentary time. We explored the relative importance of socio-demographic correlates of sedentary time in adults across Europe. We used data from 26,617 adults who participated in the 2013 Special Eurobarometer 412 "Sport and physical activity". Participants from all 28 EU Member States were randomly selected and interviewed face-to-face. Self-reported sedentary time was dichotomized into sitting less or >7.5h/day. A Chi-squared Automatic Interaction Detection (CHAID) algorithm was used to create a tree that hierarchically partitions the data on the basis of the independent variables (i.e., socio-demographic factors) into homogeneous (sub)groups with regard to sedentary time. This allows for the tentative identification of population segments at risk for unhealthy sedentary behaviour. Overall, 18.5% of the respondents reported sitting >7.5h/day. Occupation was the primary discriminator. The subgroup most likely to engage in extensive sitting were higher educated, had white-collar jobs, reported no difficulties with paying bills, and used the internet frequently. Clear socio-demographic profiles were identified for adults across Europe who engage in extended sedentary time. Furthermore, physically active participants were consistently less likely to engage in longer daily sitting times. In general, those with more indicators of higher wealth were more likely to spend more time sitting

Droplet Fluctuations in the Morphology and Kinetics of Martensites

We derive a coarse grained, free-energy functional which describes droplet configurations arising on nucleation of a product crystal within a parent. This involves a new `slow' vacancy mode that lives at the parent-product interface. A mode-coupling theory suggests that a {\it slow} quench from the parent phase produces an equilibrium product, while a {\it fast} quench produces a metastable martensite. In two dimensions, the martensite nuclei grow as `lens-shaped' strips having alternating twin domains, with well-defined front velocities. Several empirically known structural and kinetic relations drop out naturally from our theory.Comment: 4 pages, REVTEX, and 3 .eps figures, compressed and uuencoded, Submitted to Phys. Rev. Let

Clinical assessment of decision-making capacity in acquired brain injury with personality change

Assessment of decision-making capacity (DMC) can be difficult in acquired brain injury (ABI) particularly with the syndrome of organic personality disorder (OPD) (the “frontal lobe syndrome”). Clinical neuroscience may help but there are challenges translating its constructs to the decision-making abilities considered relevant by law and ethics. An in-depth interview study of DMC in OPD was undertaken. Six patients were purposefully sampled and rich interview data were acquired for scrutiny using interpretative phenomenological analysis. Interview data revealed that awareness of deficit and thinking about psychological states can be present. However, the awareness of deficit may not be “online” and effectively integrated into decision-making. Without this online awareness of deficit the ability to appreciate or use and weigh information in the process of deciding some matters appeared absent. We argue that the decision-making abilities discussed are: (1) necessary for DMC, (2) threatened by ABI , and (3) assessable at interview. Some advice for practically incorporating these abilities within assessments of DMC in patients with OPD is outlined

Regional and hemispheric impacts of anthropogenic and biomass burning emissions on summertime CO and O3 in the North Atlantic lower free troposphere

Copyright © 2004 American Geophysical Union. All Rights Reserved.We report summertime measurements of CO and O3 obtained during 2001–2003 at the PICO-NARE mountaintop station in the Azores. Frequent events of elevated CO mixing ratios were observed. On the basis of backward trajectories arriving in the free troposphere and global simulations of biomass burning plumes, we attribute nearly all these events to North American pollution outflow and long-range transport of biomass burning emissions. There was a high degree of interannual variability in CO levels: median [CO] ranged from 65 ppbv in 2001 to 104 ppbv in 2003. The highest concentrations were associated with transport of Siberian fire emissions during summer 2003, when Siberian fire activity was unusually high. Ozone mixing ratios also increased (by up to ∼30 ppbv) during the fire events. These findings demonstrate the significant hemispheric scale impact that biomass burning events have on background CO and O3 levels. O3 enhancements of similar magnitude were also observed in North American pollution outflow. O3 and CO were correlated during North American outflow events, with a slope averaging 1.0 (d[O3]/d[CO], ppbv/ppbv) when no fire impact was present. This slope is more than 80% larger than early 1990s observations made in the eastern United States and nearshore outflow region, even after accounting for declining U.S. CO emissions and for CO loss during transport to the Azores, and is not consistent with simple dilution of U.S. outflow with marine background air. We conclude that a significantly larger amount of O3 production occurred in the air sampled during this study, and we suggest several potential reasons for this, each of which could imply potentially significant shortcomings in current estimates of the hemispheric impact of North American emissions on tropospheric ozone and should be evaluated in future studies

Harmonized Landsat/Sentinel-2 Reflectance Products for Land Monitoring (Invited)

Many land applications require more frequent observations than can be obtained from a single 'Landsat class' sensor. Agricultural monitoring, inland water quality assessment, stand-scale phenology, and numerous other applications all require near-daily imagery at better than 1ha resolution. Thus the land science community has begun expressing a desire for a '30-meter MODIS' global monitoring capability. One cost-effective way to achieve this goal is via merging data from multiple, international observatories into a single virtual constellation. The Harmonized Landsat/Sentinel-2 (HLS) project has been working to generate a seamless surface reflectance product by combining observations from USGS/NASA Landsat-8 and ESA Sentinel-2. Harmonization in this context requires a series of radiometric and geometric transforms to create a single surface reflectance time series agnostic to sensor origin. Radiometric corrections include a common atmospheric correction using the Landsat-8 LaSRC/6S approach, a simple BRDF adjustment to constant solar and nadir view angle, and spectral bandpass adjustments to fit the Landsat-8 OLI reference. Data are then resampled to a consistent 30m UTM grid, using the Sentinel-2 global tile system. Cloud and shadow masking are also implemented. Quality assurance (QA) involves comparison of the output 30m HLS products with near-simultaneous MODIS nadir-adjusted observations. Prototoype HLS products have been processed for approximately 7% of the global land area using the NASA Earth Exchange (NEX) compute environment at NASA Ames, and can be downloaded from the HLS web site (https://hls.gsfc.nasa.gov). A wall-to-wall North America data set is being prepared for 2018. This talk will review the objectives and status of the HLS project, and illustrate applications of high-density optical time series data for agriculture and ecology. We also discuss lessons learned from HLS in the general context of implementing virtual constellations

Staphylococcus aureus in the oral cavity: a three-year retrospective analysis of clinical laboratory data

OBJECTIVE: A retrospective analysis of laboratory data to investigate the isolation of Staphylococcus aureus from the oral cavity and facial area in specimens submitted to a regional diagnostic oral microbiology laboratory. METHODS: A hand search of laboratory records for a three-year period (1998-2000) was performed for specimens submitted to the regional diagnostic oral microbiology laboratory based at Glasgow Dental Hospital and School. Data were collected from forms where S. aureus was isolated. These data included demographics, referral source, specimen type, methicillin susceptibility and clinical details. RESULTS: For the period 1998-2000, there were 5,005 specimens submitted to the laboratory. S. aureus was isolated from 1,017 specimens, of which 967 (95%) were sensitive to methicillin (MSSA) and 50 (5%) were resistant to methicillin (MRSA). The 1,017 specimens were provided from 615 patients. MRSA was isolated from 37 (6%) of patients. There was an increasing incidence of S. aureus with age, particularly in the greater than 70 years age group. The most common specimen from which MSSA was isolated was an oral rinse (38%) whilst for MRSA isolates this was a tongue swab (28%). The clinical condition most commonly reported for MSSA isolates was angular cheilitis (22%). Erythema, swelling, pain or burning of the oral mucosa was the clinical condition most commonly reported for MRSA isolates (16%). Patients from whom the MSSA isolates were recovered were most commonly (55%) seen in the oral medicine clinic at the dental hospital, whilst patients with MRSA were more commonly seen in primary care settings such as nursing homes, hospices and general dental practice (51%). CONCLUSION: In line with more recent surveys, this retrospective study suggests that S. aureus may be a more frequent isolate from the oral cavity than hitherto suspected. A small proportion of the S. aureus isolates were MRSA. There were insufficient data available to determine whether the S. aureus isolates were colonising or infecting the oral cavity. However, the role of S. aureus in several diseases of the oral mucosa merits further investigation

Concern About Petrochemical Health Risk Before and After a Refinery Explosion

On March 23, 2005, a large explosion at an oil refinery in Texas City, Texas caused 15 deaths and approximately 170 injuries. Little is known about how such an industrial accident influences concern about environmental health risks. We used measures of environmental health concern about nearby petrochemical production with a sample of Texas City residents to understand patterns of concern and change in concern after an industrial accident, as well as individual and contextual factors associated with those patterns. Survey interviews with residents of Texas City, Texas (N =315) both pre- and postexplosion using a brief Concern About Petrochemical Health Risk Scale (CAPHRS) and other questions were used to collect pertinent predictor information. CAPHRS baseline, postexplosion, and change scores were compared and modeled using ordinary least squares (OLS) regression and a mixed model. Higher preexplosion CAPHRS scores were predicted by younger adults, foreign-born Hispanics, non-Hispanic blacks, lower- and middle-income groups, and those who live with someone who has worked at the petrochemical plants. Higher CAPHRS change scores are predicted by the same variables (except income), as well as proximity to, or perception of, the explosion, and reports of neighborhood damage. Findings suggest these groups’ concern scores could indicate a greater vulnerability to psychological and physical harm generated by concern and stress arising from local petrochemical activities. A clearer understanding of concern about actual environmental health risks in exposed populations may enhance the evolving theory of stress and coping and eventually enable public health professionals to develop appropriate mitigation strategies

Improving our understanding of metal implant failures: Multiscale chemical imaging of exogenous metals in ex-vivo biological tissues

Biological exposures to micro- and nano-scale exogenous metal particles generated as a consequence of in-service degradation of orthopaedic prosthetics can result in severe adverse tissues reactions. However, individual reactions are highly variable and are not easily predicted, due to in part a lack of understanding of the speciation of the metal-stimuli which dictates cellular interactions and toxicity. Investigating the chemistry of implant derived metallic particles in biological tissue samples is complicated by small feature sizes, low concentrations and often a heterogeneous speciation and distribution. These challenges were addressed by developing a multi-scale two-dimensional X-ray absorption spectroscopic (XAS) mapping approach to discriminate sub-micron changes in particulate chemistry within ex-vivo tissues associated with failed CoCrMo total hip replacements (THRs). As a result, in the context of THRs, we demonstrate much greater variation in Cr chemistry within tissues compared with previous reports. Cr compounds including phosphate, hydroxide, oxide, metal and organic complexes were observed and correlated with Co and Mo distributions. This variability may help explain the lack of agreement between biological responses observed in experimental exposure models and clinical outcomes. The multi-scale 2D XAS mapping approach presents an essential tool in discriminating the chemistry in dilute biological systems where speciation heterogeneity is expected. Significance: Metal implants are routinely used in healthcare but may fail following degradation in the body. Although specific implants can be identified as ‘high-risk’, our analysis of failures is limited by a lack of understanding of the chemistry of implant metals within the peri-prosthetic milieu. A new approach to identify the speciation and variability in speciation at sub-micron resolution, of dilute exogenous metals within biological tissues is reported; applied to understanding the failure of metallic (CoCrMo) total-hip-replacements widely used in orthopedic surgery. Much greater variation in Cr chemistry was observed compared with previous reports and included phosphate, hydroxide, oxide, metal and organic complexes. This variability may explain lack of agreement between biological responses observed in experimental exposure models and clinical outcomes